Natural cytotoxic (NC) cells and natural killer (NK) cells belong to a heterogeneous family of cytolytic effectors found in spleen, lymphnodes, and peripheral blood of non-immunized individuals. NC and NK activities have characteristics in common but are effected by different cells, utilizing different lytic mechanisms. It now seems likely that tumor necrosis factor (TNF) mediates NC activity. Experiments are proposed which will reveal whether NC activity is mediated by secreted TNF, cell-associated TNF, or both. Importantly, there is substantial evidence that NC cells function as a protective mechanism against incipient tumors. Moreover, there is reason to believe that NC activity functions in this role in conjunction with an induced, antigen-specific immune response, probably mediated by T-cells. Accordingly, we plan experiments to ascertain how NC activity can affect immune responses to tumor cells, and whether TNF can affect either the induction of an immune response, or target susceptibility to cytotoxic T-cells. Recently we found that spleen cells elaborate a factor(s) capable of rendering certain target cells NC resistant; a similar NC/TNF inhibitory activity is found in normal serum. Characterization of this factor(s) is planned since it could aid in our understanding of NC/TNF regulatory mechanisms, as well as prove valuable for treatment of cancer (i.e. blocking the NC/TNF inhibitory activity might make NC cells, or TNF, more efficient anti-cancer modalities) or prevention of diseases thought to be mediated by TNF (e.g., cachexia associated with cancer, or endotoxin-induced shock resulting from Gram-negative bacterial infections). We have also observed that certain cells which are normally sensitive to NC lysis, become resistant to NC activity when cultured at high density. We have designed experiments to ascertain whether this is a general characteristic of NC-sensitive cells, and how high density culture affects cells such that they become NC-resistant. Most importantly, we will determine whether there is a causal relationship between NC-sensitivity and the expression of contact-inhibition, or between NC resistance and contact-noninhibition. Such relationships would mark a critical prediction of anti-tumor surveillance hypotheses.